CN103140480A - Heterocyclic compounds, their preparation and their therapeutic application - Google Patents
Heterocyclic compounds, their preparation and their therapeutic application Download PDFInfo
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- CN103140480A CN103140480A CN2011800407027A CN201180040702A CN103140480A CN 103140480 A CN103140480 A CN 103140480A CN 2011800407027 A CN2011800407027 A CN 2011800407027A CN 201180040702 A CN201180040702 A CN 201180040702A CN 103140480 A CN103140480 A CN 103140480A
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- C07D239/72—Quinazolines; Hydrogenated quinazolines
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Abstract
The invention is directed to certain novel compounds, methods for producing them and methods for treating or ameliorating a kinase-mediated disorder.
Description
Technical field
The present invention relates to the method that some new compounds, their preparation method and treatment or improvement involve the obstacle of Tyrosylprotein kinase imbalance, described obstacle is for example with vascular permeability increase or blood vessel, relevant obstacle to occur.More specifically, the present invention relates to preparation method and treatment, the prevention of the triazolopyridine compounds as the replacement of selective kinase inhibitors, described compound or improve the method for kinase mediated obstacle.Particularly, described method relates to treats or improves the obstacle that involves the Tyrosylprotein kinase imbalance, comprises cardiovascular disorder, diabetes, diabetes associated disorders, diseases associated with inflammation, dysimmunity, cancer and eye disease such as retinopathy, macular degeneration or other vitreoretinal diseases etc.
Background technology
In multiple situation, liquid and cell are inflammation, tissue injury, oedema and dead significant contribution factor from the outflow of blood vessel.These situations comprise ischemic injury, toxic shock, burn, wound, allergic effect reaction and immune response.Vascular permeability partly is subjected to the adjusting of cell-cell adhesion between endotheliocyte.Monolayer endothelial cell as the vascular system lining forms the barrier of keeping blood flow compartment (blood fluid compartment), but allows the solvable factor and white corpuscle to pass through with regulative mode.The imbalance of this process causes vascular leakage to enter surrounding tissue, and this is accompanied by the inflammation relevant with the pathologic edema disease.Vascular permeability is a kind of function of meticulous adjusting, and it can actively cause protective immune response and wound healing; Yet under most pathologic conditions, a large amount of and/or long-term seepage of liquid and immunocyte move to may have serious and life-threatening consequence sometimes in tissue.
Leading edematigenous abnormal retinal blood vessel infiltration in macular area is major cause blind in following disease, and described disease is for example diabetic retinopathy, exudative macular degeneration, retinal vascular occlusion and inflammation and tumprigenicity illness.Although the various diseases process can cause vascular permeability to increase by different mechanism, known cytokine VEGF plays a significant role as the vascular leakage inductor.VEGF is described to the effective vascular permeability factor (VPF) by tumor cell secretion at first, and it stimulates the quick and reversible increase of capillary blood vessel infiltration.Vascular permeability is such as increase and VEGF Horizontal correlation in ischemic retinopathy (may be also exudative macular degeneration and uveitis), and the VEGF antagonist successfully be used for neogenesis vascular ophthalmopathy for example macular degeneration reduce retina/macular edema, make visual acuity stable or even make its enhancing in a small group patient.In recent years, disclosed the infiltrative mode of VEGF induction of vascular and verified, the vascular leakage that VEGF-induces is by the cytoplasmic protein kinases member mediation of Src proto-oncogene family.
Protein kinase plays a significant role in the adjusting of various kinds of cell process and cell function with in keeping.For example, the kinase activity molecular switch that makes adjustments cell proliferation, activation and/or differentiation.Generally admit now, various diseases is to reply (approach by overacfivity protein kinase-mediation causes) by abnormal cells to cause.
The Src kinases forms film and adheres to non-acceptor dependency family tyrosine kinase, comprise eight member: Src, Fyn, Yes, Fgr, Lyn, Hck, Lck and Blk at kinases described in Mammals, they receptor signal conduction with have vital role during cell is communicated by letter.Although most of Src kinases are by wide expression (that is, Src, Fyn, Yes), some members of described family for example Hck, Blk or Lck show limited expression.The Src kinases is as film attachment molecules switch performance keying action, and it is related with the Cellular Signaling Transduction Mediated approach with the outer clue of various kinds of cell.This is the basis that the Src kinases participates in cell proliferation and differentiation and cell adhesion and migration.
Sufficient proof is, Src protein level and Src kinase activity significantly raise in human cancer, and described cancer comprises breast cancer, colorectal carcinoma, carcinoma of the pancreas, some B-chronic myeloid leukemia and lymphoma, gastrointestinal cancer, nonsmall-cell lung cancer, bladder cancer, prostate cancer and ovarian cancer, melanoma and sarcoma.Therefore, people infer that coming the disabling signal conduction by the kinase activity that suppresses Src will be the effective means of regulating the abnormal approach that orders about the cell tumour transformation.
Similarly, sufficient proof is, and the Src-family kinase is also important for the signal conduction in immunocyte acceptor downstream.The same with Lck also, Fyn participates in the TCR signal conduction of T cell.Hck and Fgr participate in causing neutrophilic granulocyte to activate in the signal conduction of Fc γ acceptor.Lyn and Src also participate in the signal conduction of Fc γ acceptor, cause the release of histamine and other allergy medium.These find hint, and the Src family kinase inhibitors can be used for treating allergic disease and asthma.
According to the impact of VEGF on vascular permeability, several pieces of reports support the Src kinases in the developing effect of oedema.For example, in mouse, Src (but not Fyn) disappearance or blocking-up Src make the cerebral edema after permanent cerebral ischemia reduce approximately 55%.Recently, it is found that PP1 (a kind of Src tyrosine kinase inhibitor) reduces oedema, reduces the expression that hemato encephalic barrier (BBB) destroyed and reduced VEGF.Similarly, the people such as Scheppke have proved, and the Src kinases is the important medium of the retinal vessel seepage of the VEGF-retinal vessel seepage of inducing and local asphyxia-induce.
In addition, in vascular endothelial cell, the Src Tyrosylprotein kinase mediates the conduction of vegf receptor signal fully.Therefore, stimulate the vegf receptor or other somatomedin that are positioned on endotheliocyte or progenitor cell to cause the Src kinase activator, and described Src kinase activator causes the blood vessel generation, in retinal diseases and keratopathy, this may be a kind of harmful replys and this is replied and has obviously caused tumour to worsen and transitivity moves.
Disclosed several compounds of regulating or more specifically suppressing kinase activity, they are particularly potential therapeutical agents of cancer of kinase mediated obstacle.
For example, WO2001038315 has described amido quinazoline, and it is the inhibitor of cyclin-dependant kinase.
WO2008068507 has described the pyridyl quinazoline, and it is the Raf serine/threonine kinase inhibitor that is used for the treatment of cancer.
WO2008079988 has described quinazoline, and it is to be used for the treatment of for example PDK1 kinase inhibitor of cancer of proliferative disease.
WO2006118256 has described quinazoline derivant, and it is for being used for sucking and being used for the treatment of the p38MAPK inhibitor of various diseases associated with inflammation and cancer.
WO2006039718 has described the nitrogenous bicyclic compound of aryl, and the disease that it is used for the treatment of protein kinase-mediation comprises inflammation, cancer and associated conditions.
WO2005037285 has described the dibasic bicyclic heterocycles of 2,6-, and it is to be used for the treatment of for example Raf serine/threonine kinase inhibitor of cancer of obstacle.
WO2009046448 has described the PI3 modulators of kinase activity, and it has the amido quinazoline of replacement on the pyrimidine part of quinazoline two rings.
WO2009084695 has described the amido quinazoline derivatives that is replaced by two non-aromatic substituting groups.
WO2008020203 has described the amido quinazoline derivatives that is replaced by pyridine on the phenyl moiety of quinazoline two rings, it has B-Raf and suppresses active.
US20100093698 has described at the substituted aminotriazole in 5-position and pyridine derivate, and it has the Syk kinase inhibiting activity.
WO2004065378 has described PA, and it is to be used for the treatment of for example cdk4 inhibitor of cancer, atherosclerosis and restenosis of cell proliferation sexual dysfunction.
Interestingly, WO2006024034 has described the heterogeneous ring compound derived from phentriazine, triazine, triazole He oxadiazole, for example phentriazine compound (WO2005096784) or pyrimidine compound (WO2006101977), they can suppress for example member of Src kinases family of kinases.Yet, although these medicines for the various ophthalmic diseasess for the treatment of (for example, age related macular degeneration, diabetic retinopathy, diabetic macular edema, cancer and glaucoma) as claiming useful they be lipophilic and be water-insoluble (referring to WO2006133411).Contriver according to WO2006133411, these concrete character are particularly advantageous, particularly for ophthalmic applications, because these medicines insoluble in water are (in the pH4-8 scope, water solubility is less than about 0.1mg/mL) have high capacity efficient (efficiency of loading) and insignificant seepage (this be due to the water ratio, described medicine height is assigned to for the liposome of sending them).
WO2010076238 has described mono-substituted amido quinazoline derivatives, and it has anti-src and the kinase whose good IC50 of lyn.
The Src kinase inhibitor of describing in US2005/0245524 is shiny red and is very insoluble in being suitable for the preparation of sending by eye drops.These two parameters have represented the significant drawbacks of the compound that discloses in US2005/0245524.
Eyes are organs that need strict protection.In this respect, treatment eye rear portion disease (disease of the back-of-the-eye) may be the task that drug delivery is the most difficult and tool is challenged, and the scarcity for the treatment of means has proved this point.Carry out one of drug delivery most convenient and safest form for eye drops to eye, this is because eye drops is not invasive, does not need medical science auxiliary and need the small volume drug solution.Yet, in order to be suitable for local drop-method, thus molecule must to they molecular target enough effectively, must have the reason that allows to pass cytolemma-voltinism matter and must be in aqueous medium enough solvable can being applied on cornea with the solution form.In addition, importantly described drug molecule for colourless painted to prevent ocular tissue, ocular tissue is painted finally may hinder vision as far as possible.In addition, due to the many cross reactivities between kinases, expect very that also described drug molecule suppresses directed kinases with high selectivity.
Summary of the invention
A feature of the present invention is to provide and competes medicine and compare the new compound that water solubility increases.
Another feature of the present invention is to provide the high efficiency compound particularly as the high efficiency compound of src kinase inhibitor.
Another feature of the present invention is to provide and is used for the treatment of, prevents or improve the compound that the obstacle that involves Tyrosylprotein kinase imbalance (for example increase with vascular permeability or relevant obstacle occurs blood vessel) comprises the ophthalmology obstacle.
Another feature of the present invention is to provide colourless or almost colourless, particularly colourless or almost colourless compound in solution.
Specification sheets is below partly described other features and advantages of the present invention, and a part of content because becoming apparent maybe, can be known by implementing the present invention in described description.Will be by element and combination, element and the combination particularly pointed out in specification sheets and the claim of enclosing realize and complete purpose of the present invention and other advantage.
The present invention relates to following general formula compound and prodrug thereof:
Wherein
A be aryl, Heterocyclylalkyl ,-Heterocyclylalkyl of N-aryl, – O-aryl, heteroaryl or fractional saturation;
B is heteroaryl or aryl;
R1 and R2 are connected to ring upward and expression independently of one another:
-H，
-OH，
Halogen atom,
-O (C
1-C
6) alkyl,
(C
1-C
6) alkyl,
-(CH
2)
nOH，
-NH
2，
The N-oxide compound, wherein said nitrogen-atoms belongs to A,
Condition be only when A be Heterocyclylalkyl, – O-aryl, heteroaryl or part replace Heterocyclylalkyl the time, R1 and R2 can be hydrogen atom;
R3, R4 and R5 are independently of one another:
-H，
-(CH
2)
nOH，
-O (C
1-C
6) alkyl,
-(CH
2)
n-CO-Heterocyclylalkyl,
-OH，
-Heterocyclylalkyl-(CH
2)
n-OH,
-(C
1-C
6) alkyl,
-(CH
2)
n-Heterocyclylalkyl,
-(CH
2)
n-Heterocyclylalkyl-(CH
2)
n-OH,
-O-(CH
2)
n-Heterocyclylalkyl,
The N-oxide compound, wherein said nitrogen-atoms belongs to B,
-O-(CH
2)
n-CO-Heterocyclylalkyl,
-O-(CH
2)
n-OH，
-O (C
1-C
6) alkyl-NR7R8,
-(C
1-C
6) alkyl-NR7R8,
Condition is that at least two in R3, R4 and R5 is not hydrogen when A and B are aryl;
R6 is H, – O (C
1-C
6) alkyl or (C
1-C
6) alkyl;
R7 and R8 are H or (C independently of one another
1-C
6) alkyl;
N is 1,2 or 3;
X is N or C; With
Y is C or key.
According to an embodiment, the present invention relates to the prodrug of formula (I) compound and formula (I) compound:
Wherein
A is phenyl;
B is phenyl, pyridyl or pyrimidyl,
R1 and R2 represent independently of one another:
-H，
-OH，
Halogen atom,
Condition is that R1 and R2 are not hydrogen atom simultaneously;
R3, R4 and R5 are independently of one another:
-H，
-(CH
2)
nOH，
-O (C
1-C
6) alkyl,
-(CH
2)
n-CO-Heterocyclylalkyl,
-OH，
-Heterocyclylalkyl-(CH
2)
n-OH,
-(C
1-C
6) alkyl,
-(CH
2)
n-Heterocyclylalkyl,
-(CH
2)
n-Heterocyclylalkyl-(CH
2)
n-OH,
-O-(CH
2)
n-Heterocyclylalkyl,
The N-oxide compound, wherein said nitrogen-atoms belongs to B,
-O-(CH
2)
n-CO-Heterocyclylalkyl,
-O-(CH
2)
n-OH，
-O (C
1-C
6) alkyl-NR7R8,
-(C
1-C
6) alkyl-NR7R8,
-or R3 and R4 form the optional fused bicyclic (for example, indoles or benzoglyoxaline) that is replaced by R5 together with B,
Condition is that R3, R4 and R5 are not hydrogen when A and B are aryl;
R6 is H ， – O (C
1-C
6) alkyl or (C
1-C
6) alkyl;
R7 and R8 are H or the optional (C that replaces independently of one another
1-C
6) alkyl, (the C of described optional replacement
1-C
6) the optional cycloalkyl that forms of alkyl;
N is 1,2 or 3;
X is N or C; With
Y is CH or covalent linkage.
Of the present invention should can the expression by following formula (Ia) by the group compound:
Wherein define according to any embodiment or their combination in R1, R2, R3, R4, R5, R6, R7 and R8 such as the present invention.
In the context of the present specification, the term that defines of the below is appreciated that and has defined implication after each term:
Unless-context is otherwise noted, " one " or " a kind of " are used for expression " at least one (kind) ", " first (kind) at least ", " one or more (kind) " or " a plurality of (kind) " mentioned compound or step.More specifically, " at least one (kind) " and " one or more (kind) " refers to one or greater than the number of, particularly preferably is one, two or three (kind);
-the application use Anywhere " and/or " comprise following implication: " and be connected, " or " with being connected all or other combination arbitrarily of the element that connected by described term ";
-" approximately " or " approximately " refer to set-point or scope 20% in, in preferred 10% and more preferably in 5%;
-when " comprising (comprising) ", " containing (containing) " are used for defining product, composition and method, its expection refers to that described product, composition and method comprise mentioned compound or step, but does not get rid of other compound or step;
-" dispose (treatment) " or " treatment (treating) " comprise and preventing and/or treating.Therefore, the compositions and methods of the invention are not limited to the treatment application and can be used in prophylactic applications.therefore, " treatment " or " disposal " state (state), obstacle or illness comprise: the state that (i) prevents or postpone to develop in the experimenter, the appearance of the clinical symptom of obstacle or illness, described experimenter may suffer from or easily suffer from described state, obstacle or illness but also do not experience or show described state, clinical or the inferior clinical symptom of obstacle or illness, (ii) suppress described state, obstacle or illness, namely stop described disease or its at least a clinical or the development of inferior clinical symptom or the described development of slowing down, perhaps (iii) alleviates described disease, namely, make described state, obstacle or illness or its at least a clinical or inferior clinical symptom disappear,
-" patient " and " experimenter who has this to need " expection refer to any animal; Vertebrates (a member of mammal) and include but not limited to that domestic animal (for example, ox, pig, sheep, horse, dog and cat), primate comprise the people for example.Term " patient ", " experimenter who has this to need " never are limited to specific morbid state, and it had both comprised that the patient who has developed into the disease of paying close attention to also comprised not ill patient.
-" therapeutical active compound " refers to cause for example any compound (choosing wantonly in composition) of tissue, animal or human, cell or the required biological response of organ.
-" treatment significant quantity " refers to any amount of therapeutical active compound or composition.
-" prodrug " refers to inactive form or the active any compound that is starkly lower than the form administration of the activity after its bioactivation.In case administration, described prodrug internal metabolism becomes therapeutical active compound (medicine).This process is called as bioactivation.This bioactivation divides a step or multistep to occur, namely by providing one or more metabolites to occur.Prodrug itself is not usually therapeutical active compound and at external biological response after usually can not causing corresponding treatment active compound bioactivation.According to the present invention, bioactivation especially occurs in cornea.This available for example Ussing chamber (Ussing chambers) is tested.
-" halogen " refers to any one in fluorine, chlorine, bromine or iodine;
-" ring " refers to Heterocyclylalkyl, aryl or the heteroaryl that cycloalkyl, Heterocyclylalkyl, part replace;
-" cycloalkyl " refers to contain the saturated monocycle carbocyclic ring of 3 to 7 carbon atoms.The example of monocycle alkyl comprises cyclopropyl, cyclobutyl, cyclopentyl etc.;
-" Heterocyclylalkyl " refers to saturated mono-or bicyclic heterocycles, and it has 3 to 14 atoms, for example 5 to 10 atoms or 5 to 6 atoms, and comprise the heteroatoms that at least one is selected from nitrogen, oxygen and sulphur.If described Heterocyclylalkyl contains a more than heteroatoms, described heteroatoms can be identical or different.When being substituted, described part can be substituted at carbon atom or on heteroatoms; Similarly, described Heterocyclylalkyl can be connected with the remainder of molecule by carbon atom or heteroatoms.The example of Heterocyclylalkyl is tetramethyleneimine, piperidines, piperazine, morpholine etc.;
-" Heterocyclylalkyl of fractional saturation " refers to comprise at least one two key but the double key number that comprises is not enough so that it is considered to the Heterocyclylalkyl of aromaticity;
That-" aryl " comprises is single-and the bicyclic aromatic carbocyclic ring.The example of aryl comprises phenyl, naphthalene-1-base, naphthalene-2-base;
-" heteroaryl " refers to aromatics list-or aryl bicyclic, and wherein each ring comprises 5 to 10 atoms, 5 to 6 atoms for example, and comprise the heteroatoms that at least one is selected from nitrogen, oxygen and sulphur.If described heteroaryl contains a more than heteroatoms, described heteroatoms can be identical or different.When being substituted, described part can be substituted at carbon atom or on heteroatoms; Similarly, described heteroaryl can be connected with the remainder of molecule by carbon atom or heteroatoms.The example of heteroaryl is pyridine, indoles, cumarone, oxazole, triazole, pyrimidine, pyrazoles, indazole, benzoglyoxaline etc.;
-at " (C
1-C
6) " in, described numeral has defined the possible number of the atom that exists in described chain or described ring;
-" alkyl " be saturated aliphatic groups, and it is straight or branched.For example, C
1-C
6Alkyl represents to comprise the straight or branched carbochain of 1 to 6 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group.
The application's term " compound " refers to formula I compound or its medicinal prodrug substantially.
Formula (I) compound as theme of the present invention comprises first group of compound, and it is following formula (II) compound:
Formula (I) compound comprises second group of compound, and it is following formula (III) compound:
Formula (I) compound comprises the 3rd group of compound, and it is following formula (IV) compound:
The compounds of this invention comprises the 4th group of compound, and it is 3 and 6 those compounds with R1 and R2 at phenyl ring.
Formula (I) compound comprises the 5th group of compound, and it is following formula (V) compound:
Formula (I) compound comprises the 6th group of compound, and it is following formula (VI) compound:
Formula (I) compound comprises the 7th group of compound, and it is following formula (VII) compound:
Formula (I) compound comprises the 8th group of compound, and it is following formula (VIII) compound:
Formula (I) compound comprises the 9th group of compound, and it is following formula (IX) compound:
Formula (I) compound comprises the tenth group of compound, and it is following formula (X) compound:
Formula (I) compound comprises that is one group of compound, and it is following formula (XI) compound:
Wherein R10 is:
-H,
-(CH
2)
nOH,
-O (C
1-C
6) alkyl,
-(CH
2)
n-CO-Heterocyclylalkyl,
-OH,
-Heterocyclylalkyl-(CH
2)
n-OH,
-(C
1-C
6) alkyl,
-(CH
2)
n-Heterocyclylalkyl,
-(CH
2)
n-Heterocyclylalkyl-(CH
2)
n-OH,
-O-(CH
2)
n-Heterocyclylalkyl,
The N-oxide compound, wherein said nitrogen-atoms belongs to B,
-O-(CH
2)
n-CO-Heterocyclylalkyl,
-O-(CH
2)
n-OH,
-O (C
1-C
6) alkyl-NR7R8, perhaps
-(C
1-C
6) alkyl-NR7R8.
In above-mentioned formula, R1, R2, R3, R4, R5, R6, R7 and R8 in the present invention according to embodiment or its combination arbitrarily definition.
Can find out from top structural formula, R6 only is connected with described two rings that encircle the left side.
In above-mentioned formula, one group of compound is that wherein R1 is that OH and R2 are those compounds of halogen atom.Concrete halogen atom is chlorine or fluorine, and chlorine particularly.
In above-mentioned formula, one group of compound is for wherein R3, R4 and R5 represent those compounds of O-alkyl or hydroxyalkyl independently of one another.
In above-mentioned formula, one group of compound shows – CH for R3, R4 and R5 earth's surface independent of one another wherein
2OH ,-O-CH
2-CH
2Those compounds of-Heterocyclylalkyl.For example, described Heterocyclylalkyl can be optional tetramethyleneimine, pyrrolidone, piperazine or the morpholine that replaces.Concrete substituting group is-(C
1-C
6) alkyl and-(C
1-C
6) hydroxyalkyl.
In above-mentioned formula, one group of compound is that wherein X represents that carbon atom and Y represent those compounds of CH.
In above-mentioned formula, one group of compound is that wherein X represents that nitrogen and Y represent those compounds of key.
In above-mentioned formula, one group of compound represents hydrogen atom or CH for R6 wherein
3Those compounds.In specific embodiment, R6 is hydrogen atom.
The compounds of this invention comprises those compounds of the embodiment of the present application, particularly following compound and their prodrug:
Compound 1:4-chloro-3-[2-(pyridin-4-yl is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol
Compound 2:4-chloro-3-[2-(pyridin-3-yl is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol
Compound 3:4-chloro-3-[2-(pyrimidine-5-base is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol
Compound 4:4-chloro-3-[2-(5-hydroxymethyl-pyridin-3-yl is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol
Compound 5:3-[2-(3,5-two-(hydroxymethyl)-phenyl amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-4-chloro-phenol
Compound 7:4-chloro-3-[2-(6-methoxyl group-pyridin-3-yl is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol
Compound 8:4-chloro-3-{2-[5-(2-(pyrrolidin-1-yl)-oxyethyl group)-pyridine-2-base is amino]-[1,2,4] triazolos [1,5-a] pyridine-6-yl }-phenol
Compound 10:4-chloro-3-(2-{6-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-pyridin-3-yl is amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenol
Compound 12:4-chloro-3-[2-(pyridine-2-base is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol
Compound 13:4-chloro-3-[2-(2-hydroxymethyl-pyridin-4-yl is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol
Compound 14:4-chloro-3-[2-(6-hydroxymethyl-pyridin-3-yl is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol
Compound 16:3-[2-(3,5-two-(hydroxymethyl)-phenyl amino)-quinazoline-6-yl]-4-chloro-phenol
Compound 17:4-chloro-3-[2-(pyridin-3-yl is amino)-quinazoline-6-yl]-phenol
Compound 18:4-chloro-3-[2-(1H-indoles-6-base is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol
Compound 19:4-[6-(2-chloro-5-hydroxyl-phenyl)-[1,2,4] triazolos [1,5-a] pyridine-2-base is amino]-pyridine-2-alcohol
Compound 20:4-chloro-3-[2-(2-methoxyl group-pyridin-4-yl is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol
Compound 21:4-chloro-3-[2-(5-hydroxymethyl-pyridin-3-yl is amino)-quinazoline-6-yl]-phenol
Compound 25:4-chloro-3-{2-[6-(2-(pyrrolidin-1-yl)-oxyethyl group)-pyridin-3-yl is amino]-[1,2,4] triazolos [1,5-a] pyridine-6-yl }-phenol
Compound 26:4-chloro-3-{2-[5-(2-(pyrrolidin-1-yl)-oxyethyl group)-pyridin-3-yl is amino]-[1,2,4] triazolos [1,5-a] pyridine-6-yl }-phenol
Compound 27:4-chloro-3-(2-{6-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-2-methyl-pyrimidine-4-yl is amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenol
Compound 28:4-chloro-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-5-methyl-phenyl amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenol
Compound 29:4-chloro-3-[2-(3,4,5-trimethoxy-phenyl amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol
Compound 30:4-chloro-3-{2-[3-(2-hydroxyl-ethyl)-3H-benzoglyoxaline-5-base is amino]-[1,2,4] triazolos [1,5-a] pyridine-6-yl }-phenol
Compound 31:4-chloro-3-[2-(pyridin-3-yl is amino)-[1,2,4] triazolos [1,5-a] pyridin-7-yl]-phenol
Compound 33:4-chloro-3-{2-[2-(2-(pyrrolidin-1-yl)-oxyethyl group)-pyridin-4-yl is amino]-[1,2,4] triazolos [1,5-a] pyridine-6-yl }-phenol
Compound 34:3-[2-(3,5-two-(hydroxymethyl)-phenyl amino)-[1,2,4] triazolos [1,5-a] pyridin-7-yl]-4-chloro-phenol
Compound 35:3-[2-(3,4-two-(hydroxymethyl)-phenyl amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-4-chloro-phenol
Compound 36:4-chloro-3-[2-(3,4,5-trimethoxy-phenyl amino)-quinazoline-6-yl]-phenol
Compound 38:4-chloro-3-(2-{2-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-pyridin-4-yl is amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenol
Compound 39:4-chloro-3-{7-methoxyl group-2-[4-(2-(pyrrolidin-1-yl)-oxyethyl group)-phenyl amino]-[1,2,4] triazolos [1,5-a] pyridine-6-yl }-phenol
Compound 40:4-chloro-3-[2-(6-methoxyl group-pyridin-3-yl is amino)-quinazoline-6-yl]-phenol
Compound 41:4-chloro-3-(2-{4-[2-(1-oxygen base-pyrrolidin-1-yl)-oxyethyl group]-phenyl amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenol
Compound 42:4-chloro-3-[2-(1H-indoles-6-base is amino)-quinazoline-6-yl]-phenol
Compound 43:4-chloro-3-[2-(2-hydroxymethyl-pyridin-4-yl is amino)-quinazoline-6-yl]-phenol
Compound 44:1-(2-{5-[6-(2-chloro-5-hydroxyl-phenyl)-[1,2,4] triazolos [1,5-a] pyridine-2-base is amino]-pyridine-2-base oxygen base }-ethyl)-pyrrolidin-2-one
Compound 45:4-chloro-3-{2-[1-(2-hydroxyl-ethyl)-1H-benzoglyoxaline-5-base is amino]-quinazoline-6-yl }-phenol
Compound 46:4-chloro-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-5-methyl-phenyl amino }-quinazoline-6-yl)-phenol
Compound 47:4-chloro-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-5-hydroxymethyl-phenyl amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenol
Compound 48: phenylformic acid 4-chloro-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-5-methyl-phenyl amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenylester
Compound 49: phenylformic acid 4-chloro-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-5-methyl-phenyl amino }-quinazoline-6-yl)-phenylester
Compound 50:4-chloro-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-5-hydroxymethyl-phenyl amino }-quinazoline-6-yl)-phenol;
With their any prodrug.
One group of prodrug is the ester of above-mentioned various compound, and the ester of the phenol ring (wherein R1/ or R2 Wei – OH) of phenylformic acid and above-mentioned formula particularly.The example of prodrug is:
Phenylformic acid 4-chloro-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-5-methyl-phenyl amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenylester; With
Phenylformic acid 4-chloro-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-5-methyl-phenyl amino }-quinazoline-6-yl)-phenylester.
According to another embodiment, the compounds of this invention when for powder type be white or light color, and when when having the aqueous solution of active concentration, described solution is colourless or transparent.
The compounds of this invention Main Function is in the src kinases.
According to another embodiment, the compounds of this invention is the src kinase inhibitor.
According to another embodiment, particular compound of the present invention has less than the about IC50 of 15nM for Src, advantageously less than about 10nM, for example less than about 1nM, less than about 0.9nM or or even less than the about IC50 of 0.5nM.
Another embodiment provides composition, and it comprises one or more the compounds of this invention and pharmaceutical carrier or aqueous medium.
Term used in this application " medicinal " refers to not produce the carrier of disadvantageous, allergic or other not expected response when delivering medicine to animal (or delivering medicine in appropriate circumstances the people)." pharmaceutical carrier " used in this application comprise in solvent, dispersion medium, dressing, antiseptic-germicide and anti-mycotic agent, isotonic agent and absorption delay agent etc. any or all.It is well known in the art using described carrier with regard to pharmaceutically active substance.The example of suitable pharmaceutical carrier is described in " Remington's Pharmaceutical Sciences " by E.W.Martin.In specific embodiment, the compounds of this invention is mixed with the pharmaceutical composition that is suitable for being administered to eye according to routine operation.Also can with replenish activeconstituents for example anti-inflammatory agent, chemotherapeutic, carcinostatic agent, immunomodulator, join in described composition based on therapeutic vaccine (gene-based therapeutic vaccine), immunotherapy product, therapeutic antibodies and/or the kinase inhibitor of gene.
According to an embodiment, the compounds of this invention is mixed with for parenteral admin, for example be mixed with for passing through intravenously, intramuscular, subcutaneous or even peritoneal injection administration.In view of the content that the present invention discloses, preparation contains the aqueous composition of one or more compounds of the present invention in those skilled in the art's technical scope.Usually, described composition can be prepared into the injection of liquor or suspension form; Also can be prepared into and be applicable to add liquid just to be prepared into the solid form of solution or suspension before injection; And described preparation also can be emulsified.
According to a specific embodiment, the compounds of this invention can be formulated as for the topical the compounds of this invention, especially for treatment ophthalmology obstacle.In view of the content that the present invention discloses, preparation contains the composition of one or more compounds of the present invention in those skilled in the art's technical scope.Usually, described composition for topical can be pressed ointment, gelifying agent or the preparation of eye drops form.Described topical ophthalmic composition may further be in-situ gel preparation.Such preparation comprises jelling agent, the concentration of described jelling agent for when with eye or when tear in the eye outside contact its effective promotion gel.Suitable jelling agent includes but not limited to for example four-substituted ethylene diamine segmented copolymer of oxyethane and propylene oxide (for example, the husky amine (poloxamine) in pool Lip river) of thermosetting polymer; Polycarbophil; With polysaccharide for example exocellular polysaccharide, carrageenin (for example, kappa carrageenan and ι-carrageenin), chitosan and seaweed gel.Phrase used in this application " but original position gel " not only comprises the low-viscosity (mobile) liquid that forms gel when contacting with eye or with the tear of eye outside, and comprise more viscous liquid for example semi-fluid and thixotropic gel, when being administered to eye, described more viscous liquid meter reveals that viscosity rolls up or the gel sclerosis.
According to another embodiment, the compounds of this invention can be mixed with for the oral administration the compounds of this invention.In view of the content that the present invention discloses, preparation contains the composition of one or more compounds of the present invention in those skilled in the art's technical scope.Usually, described composition for oral administration can be prepared by the liquor agent or suspensoid, tablet, Gyrocap and other solid form that are used for oral administration.
According to another embodiment, the compounds of this invention can be mixed with for administration the compounds of this invention in knurl.In view of the content that the present invention discloses, preparation contains the composition of one or more compounds of the present invention in those skilled in the art's technical scope.Usually, can be as above disclosed such prepares described composition for administration in knurl with regard to other route of administration.
According to another embodiment, the compounds of this invention can be mixed with for the inhalation the compounds of this invention.In view of the content that the present invention discloses, preparation contains the composition of one or more compounds of the present invention in those skilled in the art's technical scope.Usually, can be as above disclosed such prepares described composition for inhalation with regard to other route of administration.
According to another specific embodiments, the compounds of this invention will make up to form aseptic moisture ophthalmology suspensoid or solution with the acceptable sanitas of ophthalmology, viscosity intensifier, penetration enhancer, buffer reagent, sodium-chlor and water.Can prepare in the following manner the ophthalmic solution preparation: with compound dissolution in the acceptable grade of physiology is oozed water-containing buffering liquid.Further, described ophthalmic solution can comprise that the acceptable tensio-active agent of ophthalmology is to help the described compound of dissolving.In addition, described ophthalmic solution can contain to increase reagent such as hydroxy-methyl cellulose, hydroxy ethyl cellulose, HYDROXY PROPYL METHYLCELLULOSE, methylcellulose gum, polyvinylpyrrolidone of viscosity etc., thereby improves the stop of described preparation in conjunctival sac.Also jelling agent be can use, exocellular polysaccharide and xanthan gum included but not limited to.But in order to prepare aseptic eye ointment formulation, can for example in mineral oil, liquid lanolin or Chinese wax cream, activeconstituents and sanitas be made up in suitable vehicle.Preferably described compound is mixed with topical ophthalmic section's suspensoid or solution, pH is approximately 5 to 8, more preferably approximately 6.5 to approximately 7.5.Described compound is contained in common amount with 0.001wt% to 5wt% in these preparations, but preferred amount is 0.025wt% to 2wt%.Therefore, for topical application, according to the careful consideration of skilled practitioners, with 1 to 2 these formulation delivered to ocular surface, every day 1 to 4 time.
In another embodiment, it provides the obstacle that treatment involves the Tyrosylprotein kinase imbalance that the method for relevant obstacle for example occurs with vascular permeability increase or blood vessel, comprises to one or more the compounds of this invention of experimenter's drug treatment significant quantity of the described treatment of needs.
According to an embodiment, the described obstacle of Tyrosylprotein kinase imbalance that involves is for increasing relevant obstacle with vascular permeability.
According to another embodiment, relevant obstacle for occuring with blood vessel in the described obstacle of Tyrosylprotein kinase imbalance that involves.
In specific embodiment, the described obstacle that involves the Tyrosylprotein kinase imbalance is the obstacle relevant with the imbalance of src kinases.
according to an embodiment, the described obstacle that involves the Tyrosylprotein kinase imbalance is selected from for example myocardial infarction, apoplexy, congestive heart failure, ischemia injury or reperfusion injury, wound, cancer, oedema, sacroiliitis or other joint disease, transplant rejection, autoimmune disorder, burn or adult respiratory distress syndrome or adult respiratory distress syndrome (ARDS) or ophthalmology obstacle be retinopathy or vitreoretinopathy for example, diabetic retinopathy, macular edema comprises diabetic macular edema, macular degeneration, glaucoma, vascular leak syndrome, diseases associated with inflammation or oedema.
In another embodiment, it provides treatment and vascular permeability to increase the method for relevant ophthalmology obstacle, comprises to one or more the compounds of this invention of experimenter's drug treatment significant quantity of the described treatment of needs.
In another embodiment, it provides treatment to suffer from cancer or be in the method for suffering from the experimenter in risk of cancer, comprises to one or more the compounds of this invention of described experimenter's drug treatment significant quantity, thereby treats described experimenter.
In another embodiment, the method that it provides treatment to suffer from oedema and/or blood vessel generation or be in the experimenter in the risk of suffering from oedema and/or blood vessel generation, comprise to one or more the compounds of this invention of described experimenter's drug treatment significant quantity, thereby treat described experimenter.
In another embodiment, it provides treatment to suffer from macular degeneration or be in the method for suffering from the experimenter in the macular degeneration risk, comprises to one or more the compounds of this invention of described experimenter's drug treatment significant quantity, thereby treats described experimenter.
In another embodiment, it provides it to provide treatment to suffer from diabetic retinopathy or be in the method for suffering from the experimenter in the diabetic retinopathy risk, comprise to one or more the compounds of this invention of described experimenter's drug treatment significant quantity, thereby treat described experimenter.
In another embodiment, it provides it to provide treatment to suffer from macular edema or be in the method for suffering from the experimenter in the macular edema risk, comprise to one or more the compounds of this invention of described experimenter's drug treatment significant quantity, thereby treat described experimenter.
In another embodiment, it provides it to provide treatment to suffer from glaucoma or be in the method for suffering from the experimenter in the glaucoma risk, comprises to one or more the compounds of this invention of described experimenter's drug treatment significant quantity, thereby treats described experimenter.
In another embodiment, it provides it to provide treatment to suffer from retinopathy or be in the method for suffering from the experimenter in the retinopathy risk, comprise to one or more the compounds of this invention of described experimenter's drug treatment significant quantity, thereby treat described experimenter.
In another embodiment, it provides it to provide treatment to suffer from vitreoretinopathy or be in the method for suffering from the experimenter in the vitreoretinopathy risk, comprise to one or more the compounds of this invention of described experimenter's drug treatment significant quantity, thereby treat described experimenter.
In another embodiment, it provides it to provide treatment to suffer from diseases associated with inflammation or be in the method for suffering from the experimenter in the diseases associated with inflammation risk, comprise to one or more the compounds of this invention of described experimenter's drug treatment significant quantity, thereby treat described experimenter.
In another embodiment, it provides treatment to comprise the method for ophthalmology obstacle and cancer with the relevant obstacle of vascular permeability defective (compromised vascular permeability), comprises to one or more compounds of the present invention of the significant quantity of experimenter's drug treatment of the described treatment of needs and following drug regimen: anti-inflammatory agent, chemotherapeutic, carcinostatic agent, immunomodulator, therapeutic vaccine, immunotherapy product, therapeutic antibodies and/or kinases inhibitor based on gene.
Preferably come administration the compounds of this invention (especially for ophthalmic applications) by topical.Yet the present invention is not limited to local delivery, sends because it for example also comprises in intraocular and periocular injections, systemic delivery (for example, oral or other parenteral approach for example subcutaneous administration, intramuscular administration, intravenous administration) or knurl.
In another embodiment, it provides the method for sending the compounds of this invention to the eye rear portion, described method comprise preparation comprise medicine effective quantity at least a the compounds of this invention composition and send described composition to the described experimenter who sends of needs.
In another embodiment, it provides the method for sending the compounds of this invention in knurl, and described method comprises the composition for preparing at least a the compounds of this invention that comprises medicine effective quantity and sends described composition to the described experimenter's who sends of needs tumour.
In order to prepare the present composition, and more specifically prepare ophthalmic composition or anti-tumor compositions, one or more compounds of the present invention for the treatment of significant quantity are placed in vehicle known in the art.For example, the topical ophthalmic section preparation that contains steroid is disclosed in US5, and in 041,434, and the sustained release ophthalmic preparation of the high-molecular weight polymer of ophthalmological and formation high-viscosity gel has been disclosed in US4, in 271,143 and US4,407,792.In addition, GB2007091 has described the ophthalmic composition of gel form, and it comprises the aqueous solution of carboxy vinyl polymer, water-soluble alkaline material and ophthalmological.Selectively, US4,615,697 have disclosed controlled release composition and based on biological adhesive and the therapeutical agent using method of anti-inflammatory agent for example.
Concentration in the composition of the usage quantity of the compounds of this invention and use in the methods of the invention thereof depends on selected solvating agent, delivery system or equipment, patient's clinical disease, side reaction and the stability of described compound in described composition.Therefore, the doctor adopts the dosage contain the suitable preparation of proper concn the compounds of this invention and to select institute's preparation, depends on for given patient or for similar type patient's clinical experience.
In another embodiment, it provides the method for preparing one or more compounds of the present invention or its prodrug.
There is the synthetic route of many preparation the compounds of this invention, but all depends on the known chemical knowledge of synthetic organic chemist.Therefore, can and well known to a person skilled in the art the synthetic compound that is represented by formula I of operation according to the operation of describing in document.typical documents and materials are " Advanced organic chemistry ", the 4th edition (Wiley), J March, " Comprehensive Organic Transformation ", the 2nd edition (Wiley), R.C.Larock, " Handbook of Heterocyclic Chemistry ", the 2nd edition (Pergamon), A.R.Katritzky), survey article is for example at " Synthesis ", " Acc.Chem.Res. ", the article of finding in " Chem.Rev ", or the original data of being identified by the retrieval of online normative document or from the secondary publications data document of " Chemical Abstracts " or " Beilstein " for example.Can by with the embodiment of the present application in regard to the synthetic the compounds of this invention of the similar method of some representative compound illustrational those methods of institute.Those skilled in the art can utilize operation and the known operation that embodiment partly describes to prepare the compound that the application discloses.
In another embodiment, it provides test kit, described test kit comprises wrapping material and the composition that is contained in described wrapping material, wherein said wrapping material comprise label, described label indicates described composition and can be used for treating the obstacle relevant with the vascular permeability defective, and wherein said composition comprises one or more the compounds of this invention.
in another embodiment, it provides test kit, described test kit comprises wrapping material and the composition that is contained in described wrapping material, described in wrapping material comprise label, described label indicates described composition and can be used for treating the obstacle relevant with the vascular permeability defective, and wherein said composition comprises one or more the compounds of this invention, described obstacle is selected from myocardial infarction, apoplexy, congestive heart failure, ischemia injury or reperfusion injury, cancer, sacroiliitis or other joint disease, retinopathy or vitreoretinopathy, macular degeneration, autoimmune disorder, vascular leak syndrome, diseases associated with inflammation, oedema, transplant rejection, burn or adult respiratory distress syndrome or adult respiratory distress syndrome (ARDS).
In a specific embodiment, it provides test kit, described test kit comprises wrapping material and the composition that is contained in described wrapping material, wherein said wrapping material comprise label, described label indicates described composition and can be used for treating the ophthalmology obstacle relevant with the vascular permeability defective, and wherein said composition comprises the prodrug of one or more the compounds of this invention or one or more the compounds of this invention.
One skilled in the art will appreciate that and allow that the present invention that the application is described changes and modifies, described change and modification are different from those that the application illustrates.The present invention includes all described change and modifications.The present invention also comprise the institute mentioning separately or jointly in specification sheets or point out in steps, feature, preparation and composition, and comprise two or more arbitrarily arbitrarily and in all combinations or described step or feature of described step or feature.
The specific embodiments that scope of the present invention is not described by the application is limit, and described specific embodiments is only expected be used to illustrating purpose.Functional product, preparation and the method for being equal to is clearly in the scope of the invention that the application describes.
The method that the application describes can comprise one or more numerical ranges (for example, size, concentration etc.).A numerical range should be understood to include all numerical value in described scope, comprise the value that defines described scope and the value adjacent with described scope, the value gained of the result that described " value adjacent with described scope " obtains and the described range boundary of next-door neighbour's definition come to the same thing or basic identical.
Provide following examples and be used for illustrating preparation as the compound of theme of the present invention, but should not be understood to imply any restriction to described claim.The proton magnetic resonance (PMR) of each embodiment compound is consistent with the structure that belongs to.
Embodiment
Embodiment
1-synthesizes general formula (I) compound
1.1. general method
Steps A-in polar solvent and at-100 to 300 ° of C, most preferably at 50-150 ° of C, make 7-bromo-[1,2,4] triazolo [1,5-a] pyridine-2-base amine or 6-bromo-[1,2,4] triazolo [1,5-a] pyridine-2-base amine and the optional R1 that replaces of 1 equivalent, the coupling of R2-phenyl-boron dihydroxide
Step B – is in polar solvent and at-100 ° of C to 300 ° of C, and most preferably 50-150 ° of C, make (R3, R4, R5)-bromo-benzene that replaces and the 7-phenyl of the optional replacement of 1 equivalent (R1, R2 replaces)-[1,2,4] triazolo [1,5-a] pyridine-2-base amine or 6-phenyl (R1, R2 replaces)-[1,2,4] triazolo [1,5-a] pyridine-2-base amine coupling
Formula I compound and be by the method preparation described in embodiment or known as document (for example by itself for the preparation of their initial substance, in standard operation, Houben-Weyl for example, Methoden der Organischen Chemie[Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley﹠amp; Sons, Inc., New York) in the method preparation described, more precisely, be known and be suitable for preparing under the condition of described reaction.The application also can the known version of use itself, but the application is not described in more detail described version.
If necessary, but also original position is formed for the initial substance of described method, namely they is not separated from reaction mixture but they are further changed accepted way of doing sth I compound immediately.On the other hand, can progressively carry out described reaction.
Preferably, the described reaction of described compound is carried out under solvent exists, and described solvent is preferably inertia under reaction conditions separately.The example of appropriate solvent is for example hexane, sherwood oil, benzene, toluene or dimethylbenzene of hydrocarbon; Hydrochloric ether is trieline, 1 for example, 2-ethylene dichloride, tetrachloromethane, chloroform or methylene dichloride; Alcohol is methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol or the trimethyl carbinol for example; Ether, for example ether, isopropyl ether, tetrahydrofuran (THF) (THF) Huo diox; Glycol ethers is ethylene glycol monomethyl ether or ethylene glycol monoethyl ether or glycol dimethyl ether (diglyme) for example; Ketone, for example acetone or butanone; Acid amides is ethanamide, N,N-DIMETHYLACETAMIDE, dimethyl formamide (DMF) or N-Methyl pyrrolidone (NMP) for example; Nitrile, for example acetonitrile; Sulfoxide, for example dimethyl sulfoxide (DMSO) (DMSO); Nitro-compound, for example Nitromethane 99Min. or oil of mirbane; Ester, the mixture of the mixture of for example ethyl acetate, or described solvent or described solvent and water.Usually polar solvent preferably.The example of suitable polar solvent is hydrochloric ether, alcohol, glycol ethers, nitrile, acid amides and sulfoxide or their mixture.Be more preferably particularly dimethyl formamide (DMF) of acid amides.
As mentioned above, temperature of reaction depends on reactions steps and the condition of using between approximately-100 ° of C to 300 ° of C.
Reaction times usually at several minutes to a couple of days scope, depend on the reactivity of each compound and reaction conditions separately.The suitable reaction times can be easily by methods known in the art for example reaction monitoring determine.Based on the temperature of reaction that provides above, the suitable reaction times is usually in 10 minutes to 48 hours scopes.
Can choose wantonly after described each reactions steps of the application and carry out one or more post-processing operation and/or lock out operation.Suitable described operation is known in the art, for example from standard operation such as Houben-Weyl, and Methoden der organischen Chemie[Methods of Organic Chemistry], Georg-Thieme-Verlag, the operation of Stuttgart.Chromatography and drying operation that the example of described operation includes but not limited to evaporating solvent, distillation, crystallization, fractional crystallization, extracting operation, washing operation, boiling operation (digesting procedure), filter operation, chromatography, undertaken by HPLC, particularly vacuum-drying operation and/or high temperature drying operation.
Enumerating of abbreviation and shortenings:
AcOH: acetic acid; Anh: anhydrous; Atm: normal atmosphere; BOC: tertbutyloxycarbonyl; CDI:1, the 1'-carbonyl dimidazoles; Conc: dense; D: day; Dec: decompose; DMAC:N, the N-N,N-DIMETHYLACETAMIDE; DMPU:1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (IH)-pyrimidone; DMF:N, dinethylformamide; DMSO: dimethyl sulfoxide (DMSO); DPPA: azide diphenyl phosphate; EDCI:1-(3-dimethylaminopropyl)-3-ethyl carbodiimide; EtOAc: ethyl acetate; EtOH: ethanol (100%); Et
2O: ether; Et
3N: triethylamine; H: hour; MeOH: methyl alcohol; Pet.Ether: sherwood oil (boiling spread is 30-60 ° of C); Temp.: temperature; THF: tetrahydrofuran (THF); TFA: trifluoroacetic acid; Tf: trifyl.
Can prepare compound of Formula I of the present invention according to following steps A and B (disclosing above) and embodiment.In ownership system Preparation Method, all initial substances are known and can be easily prepared by known initial substance.
1.2. intermediate
In ownership system Preparation Method, all initial substances are all known maybe can being prepared by known initial substance by following general method,
A kind of method is:
Can prepare described compound by general method according to the following operation of describing in WO2007/095588 (Novartis).
Perhaps:
Can be according to J.Heterocyclic Chem.34,385 (1997) the middle following operations of describing prepare described compound by general method.
Method 1:
Synthetic intermediate 1:6-(2-chloro-5-methoxyl-phenyl)-[1,2,4] triazolos [1,5-a] pyridine-2-base amine
To 2-chloro-5-methoxyl-phenyl-boron dihydroxide (3.38g, 22.5mmol, 1.5eq), 6-bromo-[1,2,4] triazolos [1,5-a] pyridine-2-base amine (3.2g, 15mmol, 1eq) and Na
2CO
3(6.36g, 60mmol, 4eq) is in 40mlDMF/10ml EtOH/10ml H
2Add 1.733g (1.5mmol, 0.1eq) tetrakis triphenylphosphine palladium in solution in the mixture of O.Reaction mixture was refluxed in argon gas 2 hours.Then it coolingly is down to room temperature and water is separated out product, filters, water, ether and pentane rinse and obtain buff powder (3.21g, 13mmol, 90% yield).
Intermediate 2:7-(2-chloro-5-methoxyl-phenyl)-[1,2,4] triazolo [1,5-a] pyridine-2-base amine, according to regard to the disclosed method of intermediate 1 from 7-bromo-[1,2,4] triazolo [1,5-a] pyridine-2-base amine begins synthetic described compound 7-(2-chloro-5-methoxyl-phenyl)-[1,2,4] triazolo [1,5-a] pyridine-2-base amine.
Synthetic intermediate 3:3-(2-amino-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-4-chloro-phenol
Carefully adding 60ml concentration in the suspension that is cooled to 0 ° of C of 5.560g (20.24mmol, 1eq) 6-(2-chloro-5-methoxyl-phenyl)-[1,2,4] triazolos [1,5-a] pyridine-2-base amine in the 90ml methylene dichloride is the 1M BBr of 1M
3Solution.With solution stirring 2 hours.Then by adding saturated NaHCO
3Solution is adjusted to pH8 with pH.The product that filtration is separated out also washs with ether, and drying obtains 4.856g (19mmol, 92%) white powder.
(2-amino-[1 for intermediate 4:3-, 2,4] triazolo [1,5-a] pyridin-7-yl)-4-chloro-phenol, according to the method that discloses with regard to institute's intermediate 3 from 7-(2-chloro-5-methoxyl-phenyl)-[1,2,4] triazolo [1,5-a] pyridine-2-base amine begins synthetic 3-, and (2-amino-[1,2,4] triazolo [1,5-a] pyridin-7-yl)-4-chloro-phenol.
Also can be by the general method 2 described compounds of preparation.
Method 2:
Synthetic intermediate 5:6-(2-chloro-5-methoxyl-phenyl)-quinazoline-2-base amine
To 2-chloro-5-methoxyl boric acid (14.42g, 77.34mmol, 1.5eq), 6-bromo-quinazoline-2-base amine (11.55g, 51.56mmol, 1eq) and Na
2CO
3(21.86g, 206.23mmol, 4eq) is in 120ml DMF/30ml EtOH/30ml H
2Add 2.311g (5.16mmol, 0.1eq) tetrakis triphenylphosphine palladium in solution in the mixture of O.(100 ° of C) 2 hours refluxes reaction mixture in argon gas.Then it coolingly is down to room temperature and by DCM and salt solution extraction product.Then water and ether washed product, then drying obtains 9.010g (32mmol, 61%) buff powder.
Intermediate 6:(6-(2,6-dimethyl-phenyl)-quinazoline-2-base amine), according to synthesize 6-(2,6-dimethyl-phenyl)-quinazoline-2-base amine with regard to the disclosed method of intermediate 1.
Synthetic intermediate 7:3-(2-amino-quinazolines-6-yl)-4-chloro-phenol
Carefully adding 95ml concentration in the suspension that is cooled to 0 ° of C of 9.010g (31.53mmol, 1eq) 6-(2-chloro-5-methoxyl-phenyl)-quinazoline-2-base amine in the 300ml methylene dichloride is the 1M BBr of 1M
3Solution.With solution stirring 16 hours.Then by adding saturated NaHCO
3Solution is adjusted to pH8 with pH.The product that filtration is separated out also obtains 7.596g (27.96mmol, 89%) buff powder with the ether washing.
1.3. the compounds of this invention
Synthetic the compounds of this invention 5 – methods 1
To 49mg (0.05mmol, 0.03eq) Pd
2(dba)
3, 16mg (0.03mmol, 0.02eq) 5-(di-t-butyl-phosphine alkyl)-1', 3', 5'-triphenyl-1'H-[1,4'] add the pure and mild 400 μ l water of 3ml four pentyl in connection pyrazoles and 241mg (4.30mmol, 2.15eq) KOH, suspension was stirred 10 minutes at 90 ° of C.Then add 521mg (2.00mmol, 1eq) (2-amino-[1 for 3-, 2,4] triazolo [1,5-a] pyridine-6-yl)-4-chloro-phenol and 744mg (3.43mmol, 1.2eq) (3-bromo-5-hydroxymethyl-phenyl)-methyl alcohol, then add the pure and mild 400 μ l water of other 3ml four pentyl, mixture was stirred 10 hours at 90 ° of C in argon gas.With ethyl acetate extraction 3 times of described compound, use the salt water washing.Then will use Na
2SO
4Dry organic layer filters and evaporates.With described compound crystallization and filtration in methanol/ether, wash with ether.Then it is come purifying by preparation property HPLC (using ZORBAX, SB-C18 post (21,2mmx100mm, 5 μ m)).Use H
2O/ acetonitrile gradient (from 30% water to 95% acetonitrile) carries out gradient elution, and flow velocity is 50ml/mn, lasts 15 minutes, obtains 70mg (0.177mmol, 9%).
Available organic synthesis classical way begins synthetic (3-bromo-5-hydroxymethyl-phenyl)-methyl alcohol that obtains from 5-bromo-m-phthalic acid dimethyl esters (buying from Alfa Aesar).Other derivative can obtain with the organic synthesis classical way is synthetic.
Synthetic the compounds of this invention 19 – methods 2
To 49mg (0.05mmol, 0.03eq) Pd
2(dba)
3, 16mg (0.03mmol, 0.02eq) 5-(di-t-butyl-phosphine alkyl)-1', 3', 5'-triphenyl-1'H-[1,4'] add the pure and mild 400 μ l water of 3ml four pentyl in connection pyrazoles and 241mg (4.30mmol, 2.15eq) KOH, suspension was stirred 10 minutes at 90 ° of C.Then add 543mg (2.00mmol, 1eq) 3-(2-amino-quinazolines-6-yl)-4-chloro-phenol and 668mg (2.40mmol, 1.2eq) (3-bromo-5-hydroxymethyl-phenyl)-methyl alcohol, then add the pure and mild 400 μ l water of other 3ml four pentyl, mixture was stirred 10 hours at 90 ° of C in argon gas.With ethyl acetate extraction 3 times of described compound, use the salt water washing.Then use Na
2SO
4Dry organic layer filters and evaporates.With described compound crystallization and filtration in methanol/ether, wash with ether.Then it is passed through preparation property HPLC purifying (using ZORBAX, SB-C18 post (21,2mmx100mm, 5 μ m)).Use H
2O/ acetonitrile gradient (from 30% water to 95% acetonitrile) carries out gradient elution, and flow velocity is 50ml/mn, lasts 15 minutes, obtains 70mg (0.122mmol, 6%).
All compounds also can come purifying by preparation property HPLC.We have used the Agilent1200 series Semi-prep with UV detector (in the 254nM monitoring).At ZORBAX, the upper purifying compounds of SB-C18 post (21,2mmx100mm, 5 μ m).Usually use H
2O/ acetonitrile gradient (being that 5 to 50% water begins to 95% acetonitrile from scope) carries out gradient elution, and flow velocity is 50ml/mn, lasts 15 minutes.
By to the compound 1-50 of above-mentioned similar mode preparation table 1.
Measure the inhibition constant of the compounds of this invention
With Caliper Life Sciences'proprietary LabChip
TMTechnology is carried out screening and the performance test (profiling experiment) that the application describes.Caliper LC3000 and EZ Reader II equipment extensively are used in whole medicament research and development process and generate and the mechanism of action (MOA) research for detection of exploitation, elementary screening, selective screening, structure activity relationship (SARs).Described LabChip
TMTechnology is particularly suited for enzyme ' target ' for example kinases, proteolytic enzyme, Phosphoric acid esterase, histone deacetylase (HDAC), phosphodiesterase (PDE) and acyltransferase.The important benefits of described technology is separation and direct substrate and the product measured, and it allows higher signal-p-noise ratio and less false positive/negative findings.This direct measurement also allows the irrelevant enzymic activity of identification and elimination and interested kinase reaction.
General mensuration:
Described chip is hatched mobility conversion kinase assays outward and is measured the fluorescence peptide substrates to the conversion of phosphorylation product with the microtubule fluid chip.To guide on described chip by capillary pipet from the reaction mixture of a micro titer plate well, on described chip, by electrophoresis with non-phosphorylating substrate and phosphorylation product separation and detect by laser induced fluorescence.Fluorescent signal signature has in time disclosed level of response.Described phosphorylation product shifts by described chip quickly than non-phosphorylating substrate, and is shown as different peaks from the signal of described two kinds of form peptides.Caliper ' s data analysis software (HTSWA) is determined peak heights, by ratio (P/ (P+S)) and the transformation efficiency (%) of described high computational product and He Feng (peak sum).This value is for the compound hole and the control wells that exist on more described plate, thus the inhibition % of definite described compound.Be used for calculating the formula that suppresses % as follows, wherein C
100%Be the average conversion % in 100% active hole, and C
0%Be the average conversion % in 0% active hole:
((sample transforms %-C to 1-
0%)/(C
100%-C
0%)) * 100
Concrete mensuration:
LC3000Src measures
With compound dissolution in 100%DMSO and be diluted to the final required screening concentration of 25X.Carry out serial dilution to obtain to be used for the specific concentrations of concrete research.Each 1 μ L of every kind of concentration is transferred in the Greiner microtiter plate of 384-hole in duplicate.Substantially, 12 μ L enzyme buffer liquid (different supplier) (are contained purifying enzyme, 100mM HEPES (pH7.5), 1mM DTT (Calbiochem, 2333153), 10mM MgCl
2(Sigma, M-1028) or 10mM MnCl
2(Sigma, M-1787) (measuring specific) and 0.002%Brij-35 (Sigma, B4184)) add in each hole.Make compound and enzyme preincubate 15 minutes.Then add 12 μ L peptide/ATP damping fluids (to contain 100mM HEPES (pH7.5), the 1.5 fluorescein-labeled peptides of μ M (being specific to interested enzyme), ATP (at apparent K in each hole
M, Sigma, A9187) and 0.002%Brij-35) with initiation reaction.Substantially, reaction mixture was transformed with the abundance (15-40%) of acquisition peptide in linear reaction range to the phosphorylation product at incubated at room 1 – in 1.5 hours.Add 45 μ L stop buffer (containing 20mM EDTA) termination reactions.Then read plate with 12-suction pipe LabChip on LabChip3000.Obtain like that as described to transform the % value and suppress the % value, and generate the IC of compound with Graphpad Prism (4 or 5.01 version)
50Curve.With drawing IC with the non-linear curve fitting of S shape dose response-variable slope match
50Curve is also determined IC
50Value and slope slope (hillslope).
Verified, the kinase whose IC50＜200nM of the anti-Src of the compounds of this invention.Preferred compound is those compounds of the kinase whose IC50＜100nM of anti-Src.
All compounds of the present invention are white or buff powder, and become light yellowly or colourless in solution, and wherein when in solution, it has maximum concentration of ordinary dissolution at pH5.
Other data about the compounds of this invention are as follows:
Table 2
Compound 1 to 50 (comprises that prodrug (compound 48 and 49) (not being listed in table 2) shows similar solvability and cornea circulation.
Therefore, the compounds of this invention has solved the insoluble and colouring problem that above-mentioned prior art compound has.The compounds of this invention is in colourless being soluble in the again aqueous compositions that is suitable for sending by eye drops.
Shi Yan – Ussing chamber
In each experiment day, carry out penetration study with Ussing chamber.
With 3mL solution be placed on Ussing chamber in the side and the 3mL Ringer's solution is placed on is subjected in the side.The rabbit corneal tissue that newly takes out is placed between described two and half Room.
Temperature maintained 37 ° of C in whole circulation research process and provide oxygenate by continous pouring Carbogen ((oxygen/carbonic acid gas) (95/5)).
With rabbit euthanasia, take out 6 corneas and exist side by side namely and to use.Shifting out 500 μ L from Ussing chamber is subjected to side liquid and replaces with fresh buffer.Analytic sample (less than collecting rear 10 hours) immediately.
Shift out 100 μ L for side liquid from Ussing chamber and do not replace.(less than 1 hour) dilute sample and analyzing in rear 10 hours less than dilution immediately after collection.Analyze on HPLC (stationary phase: C18 (particle diameter: 3 μ m, length: 5cm, the gradient of use 5 to 95%ACN/ water (0.1% formic acid))).
When sampling period finishes, discard all corneas.
According to this scheme, proved that the compounds of this invention in these aqueous compositions easily passes through cornea, thereby made them be suitable for treating the ophthalmology indication.
Suppress neovascularization in the rat model of laser induced choroidal neovascularization (CNV)
We have studied topical the compounds of this invention 25 and reduced effect (brown Norway rat (Brown Norway), 8 ages in week) in choroidal neovascularization in rats.
First day as described in formerly, carries out CNV (Edelman and Casto2000) by Bruch ' the s film rupture that the photocoagulation laser method is brought out.In order to bring out photocoagulation, send the green laser radiation of argon by slit lamp.In every eye, approximately concentrate and apply 6-7 laser focal spot in two discus nervi optici places at distance center.Afterwards rat is used immediately topical solutions 6mg/mL (10 μ L) to process, every day twice, then put to death.After laser induced CNV 14 days, by make with isolectin B4 immunostaining fixed by horizontal retinal pigment epithelium-choroid-episcleral blood vessel is visual.
The place obtains the blood vessel through immunostaining that represents CNV at laser burn, measures the area of described blood vessel through immunostaining, estimates afterwards for the CNV that processes and replys.
By 2 trained ignorant researchists, μ m is described and changed into to the elemental area of vascular bud
2
Result
Find, compared with the control, compound 25 of the present invention makes CNV reduce 15%, thereby produces evidence to prove that the compounds of this invention is used for reducing the choroidal neovascularization relevant with moist age related macular degeneration (wet age-related macular degeneration).
Claims (22)
1. formula (I) compound or its prodrug:
Wherein
A is phenyl,
B is phenyl, pyridyl or pyrimidyl,
R1 and R2 represent independently of one another:
-H，
-OH，
Halogen atom,
Condition is that R1 and R2 are not hydrogen simultaneously;
R3, R4 and R5 are independently of one another:
-H，
-(CH
2)
nOH，
-O (C
1-C
6) alkyl,
-(CH
2)
n-CO-Heterocyclylalkyl,
-OH，
-Heterocyclylalkyl-(CH
2)
n-OH,
-(C
1-C
6) alkyl,
-(CH
2)
n-Heterocyclylalkyl,
-(CH
2)
n-Heterocyclylalkyl-(CH
2)
n-OH,
-O-(CH
2)
n-Heterocyclylalkyl,
The N-oxide compound, wherein said nitrogen-atoms belongs to B,
-O-(CH
2)
n-CO-Heterocyclylalkyl,
-O-(CH
2)
n-OH，
-O (C
1-C
6) alkyl-NR7R8,
-(C
1-C
6) alkyl-NR7R8,
-R3 and R4 form the optional fused bicyclic that is replaced by R5 together with B,
Condition is when B is phenyl, and at least two in R3, R4 and R5 is not hydrogen;
R6 is H, – O (C
1-C
6) alkyl or (C
1-C
6) alkyl;
R7 and R8 are H or the optional (C that forms the optional replacement of cycloalkyl independently of one another
1-C
6) alkyl;
N is 1,2 or 3;
X is N or C; With
Y is CH or covalent linkage.
2. the compound of claim 1, wherein said compound has following formula
Wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 1.
3. the compound of claim 1, wherein said compound has following formula
Wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 1.
4. the compound of claim 1, wherein said compound has following formula
Wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 1.
5. the compound of claim 1, wherein said compound has following formula
Wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 1.
6. the compound of claim 1, wherein said compound has following formula
Wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 1.
7. the compound of claim 1, wherein said compound has following formula
Wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 1.
8. the compound of claim 1, wherein said compound has following formula
Wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 1.
9. the compound of claim 1, wherein said compound has following formula
Wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 1.
10. the compound of claim 1, wherein said compound has following formula
Wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 1.
11. the compound of claim 1, wherein said compound has following formula
Wherein R1, R2, R3, R4, R5, R6, R7 and R8 as defined in claim 1, and wherein R10 is
-H，
-(CH
2)
nOH，
-O (C
1-C
6) alkyl,
-(CH
2)
n-CO-Heterocyclylalkyl,
-OH，
-Heterocyclylalkyl-(CH
2)
n-OH,
-(C
1-C
6) alkyl,
-(CH
2)
n-Heterocyclylalkyl,
-(CH
2)
n-Heterocyclylalkyl-(CH
2)
n-OH,
-O-(CH
2)
n-Heterocyclylalkyl,
The N-oxide compound, wherein said nitrogen-atoms belongs to B,
-O-(CH
2)
n-CO-Heterocyclylalkyl,
-O-(CH
2)
n-OH，
-O (C
1-C
6) alkyl-NR7R8, or
-(C
1-C
6) alkyl-NR7R8.
12. the compound of any one in aforementioned claim, wherein R1 is that OH and R2 are halogen atom.
13. the compound of any one in aforementioned claim, wherein R3, R4 and R5 represent O-alkyl or hydroxyalkyl independently of one another.
14. the compound of any one in aforementioned claim, wherein R3, R4 and R5 represent-CH independently of one another
2OH and-O-CH
2-CH
2-Heterocyclylalkyl.
15. the compound of any one in aforementioned claim, wherein X represents that carbon atom and Y represent CH, or wherein X represents nitrogen, and Y represents key.
16. the compound of any one in aforementioned claim, wherein R6 represents hydrogen atom or CH
3
17. the compound of any one or its prodrug in aforementioned claim, described compound is selected from:
4-chloro-3-[2-(pyridin-4-yl is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol;
4-chloro-3-[2-(pyridin-3-yl is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol;
4-chloro-3-[2-(pyrimidine-5-base is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol;
4-chloro-3-[2-(5-hydroxymethyl-pyridin-3-yl is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol;
3-[2-(3,5-two-(hydroxymethyl)-phenyl amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-4-chloro-phenol;
4-chloro-3-[2-(6-methoxyl group-pyridin-3-yl is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol;
4-chloro-3-{2-[5-(2-(pyrrolidin-1-yl)-oxyethyl group)-pyridine-2-base is amino]-[1,2,4] triazolos [1,5-a] pyridine-6-yl }-phenol;
4-chloro-3-(2-{6-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-pyridin-3-yl is amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenol;
4-chloro-3-[2-(pyridine-2-base is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol;
4-chloro-3-[2-(2-hydroxymethyl-pyridin-4-yl is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol;
4-chloro-3-[2-(6-hydroxymethyl-pyridin-3-yl is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol;
3-[2-(3,5-two-(hydroxymethyl)-phenyl amino)-quinazoline-6-yl]-4-chloro-phenol;
4-chloro-3-[2-(pyridin-3-yl is amino)-quinazoline-6-yl]-phenol;
4-chloro-3-[2-(1H-indoles-6-base is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol;
4-[6-(2-chloro-5-hydroxyl-phenyl)-[1,2,4] triazolos [1,5-a] pyridine-2-base is amino]-pyridine-2-alcohol;
4-chloro-3-[2-(2-methoxyl group-pyridin-4-yl is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol;
4-chloro-3-[2-(5-hydroxymethyl-pyridin-3-yl is amino)-quinazoline-6-yl]-phenol;
4-chloro-3-{2-[1-(2-hydroxyl-ethyl)-1H-pyrazoles-4-base is amino]-[1,2,4] triazolos [1,5-a] pyridine-6-yl }-phenol;
4-chloro-3-[2-(1-methyl isophthalic acid H-pyrazoles-4-base is amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol;
4-chloro-3-{2-[6-(2-(pyrrolidin-1-yl)-oxyethyl group)-pyridin-3-yl is amino]-[1,2,4] triazolos [1,5-a] pyridine-6-yl }-phenol;
4-chloro-3-{2-[5-(2-(pyrrolidin-1-yl)-oxyethyl group)-pyridin-3-yl is amino]-[1,2,4] triazolos [1,5-a] pyridine-6-yl }-phenol;
4-chloro-3-(2-{6-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-2-methyl-pyrimidine-4-yl is amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenol;
4-chloro-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-5-methyl-phenyl amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenol;
4-chloro-3-[2-(3,4,5-trimethoxy-phenyl amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-phenol;
4-chloro-3-{2-[3-(2-hydroxyl-ethyl)-3H-benzoglyoxaline-5-base is amino]-[1,2,4] triazolos [1,5-a] pyridine-6-yl }-phenol;
4-chloro-3-[2-(pyridin-3-yl is amino)-[1,2,4] triazolos [1,5-a] pyridin-7-yl]-phenol;
4-chloro-3-{2-[2-(2-(pyrrolidin-1-yl)-oxyethyl group)-pyridin-4-yl is amino]-[1,2,4] triazolos [1,5-a] pyridine-6-yl }-phenol;
3-[2-(3,5-two-(hydroxymethyl)-phenyl amino)-[1,2,4] triazolos [1,5-a] pyridin-7-yl]-4-chloro-phenol;
3-[2-(3,4-two-(hydroxymethyl)-phenyl amino)-[1,2,4] triazolos [1,5-a] pyridine-6-yl]-4-chloro-phenol;
4-chloro-3-[2-(3,4,5-trimethoxy-phenyl amino)-quinazoline-6-yl]-phenol;
2-{4-[6-(2-chloro-5-hydroxyl-phenyl)-[1,2,4] triazolos [1,5-a] pyridine-2-base is amino]-pyrazol-1-yl }-1-piperazine-1-base-ethyl ketone;
4-chloro-3-(2-{2-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-pyridin-4-yl is amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenol;
4-chloro-3-{7-methoxyl group-2-[4-(2-(pyrrolidin-1-yl)-oxyethyl group)-phenyl amino]-[1,2,4] triazolos [1,5-a] pyridine-6-yl }-phenol;
4-chloro-3-[2-(6-methoxyl group-pyridin-3-yl is amino)-quinazoline-6-yl]-phenol;
4-chloro-3-(2-{4-[2-(1-oxygen base-pyrrolidin-1-yl)-oxyethyl group]-phenyl amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenol;
4-chloro-3-[2-(1H-indoles-6-base is amino)-quinazoline-6-yl]-phenol;
4-chloro-3-[2-(2-hydroxymethyl-pyridin-4-yl is amino)-quinazoline-6-yl]-phenol;
1-(2-{5-[6-(2-chloro-5-hydroxyl-phenyl)-[1,2,4] triazolos [1,5-a] pyridine-2-base is amino]-pyridine-2-base oxygen base }-ethyl)-pyrrolidin-2-one;
4-chloro-3-{2-[1-(2-hydroxyl-ethyl)-1H-benzoglyoxaline-5-base is amino]-quinazoline-6-yl }-phenol;
4-chloro-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-5-methyl-phenyl amino }-quinazoline-6-yl)-phenol;
4-chloro-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-5-hydroxymethyl-phenyl amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenol;
Phenylformic acid 4-chloro-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-5-methyl-phenyl amino }-[1,2,4] triazolos [1,5-a] pyridine-6-yl)-phenylester;
Phenylformic acid 4-chloro-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-5-methyl-phenyl amino }-quinazoline-6-yl)-phenylester;
4-chloro-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-5-hydroxymethyl-phenyl amino }-quinazoline-6-yl)-phenol.
18. medicine is characterised in that it comprises the formula of any one in claim 1-17 (I) compound.
19. pharmaceutical composition is characterised in that it comprises the prodrug of the formula of any one in claim 1-17 (I) compound or formula (I) compound, and also comprises at least a pharmaceutical excipient.
20. in claim 1-17 the formula of any one (I) compound for the preparation for the treatment of, prevent or improve the medicine of following disease in purposes: the macular degeneration that retina/macular edema, age are relevant, retinal vessel seepage, diabetic retinopathy, retinal vein occlusion or the vitreoretinopathy that local asphyxia is relevant.
21. the Src kinase antagonists as defined formula (I) in claim 1-17.
22. the formula of any one (I) compound in claim 1-17 is as medicine.
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| EP10305665 | 2010-06-22 | ||
| EP10305665.1 | 2010-06-22 | ||
| PCT/EP2011/060445 WO2011161159A1 (en) | 2010-06-22 | 2011-06-22 | Heterocyclic compounds, their preparation and their therapeutic application |
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| US (1) | US20130123271A1 (en) |
| EP (1) | EP2585439A1 (en) |
| JP (1) | JP2013533237A (en) |
| KR (1) | KR20130116070A (en) |
| CN (1) | CN103140480A (en) |
| AR (1) | AR081960A1 (en) |
| AU (1) | AU2011268938A1 (en) |
| BR (1) | BR112012032721A2 (en) |
| CA (1) | CA2803496A1 (en) |
| CL (1) | CL2012003637A1 (en) |
| CO (1) | CO6660505A2 (en) |
| CR (1) | CR20120653A (en) |
| DO (1) | DOP2012000317A (en) |
| EA (1) | EA201291329A1 (en) |
| EC (1) | ECSP12012354A (en) |
| GT (1) | GT201200345A (en) |
| IL (1) | IL223721A0 (en) |
| MA (1) | MA34384B1 (en) |
| MX (1) | MX2012015305A (en) |
| NI (1) | NI201200193A (en) |
| NZ (1) | NZ605022A (en) |
| PE (1) | PE20130640A1 (en) |
| SG (1) | SG186424A1 (en) |
| TN (1) | TN2012000610A1 (en) |
| TW (1) | TW201204723A (en) |
| UY (1) | UY33461A (en) |
| WO (1) | WO2011161159A1 (en) |
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| CN109311856A (en) * | 2016-04-08 | 2019-02-05 | 贝勒医学院 | The small-molecule modulators and its application method of the steroid receptor co-activation factor |
| WO2021254464A1 (en) * | 2020-06-19 | 2021-12-23 | 南京红云生物科技有限公司 | Substituted quinazoline compound, and preparation method therefor, pharmaceutical composition thereof, and use thereof |
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| EP2343294A1 (en) | 2009-11-30 | 2011-07-13 | Bayer Schering Pharma AG | Substituted triazolopyridines |
| CN105431435A (en) * | 2013-06-07 | 2016-03-23 | 拜耳制药股份公司 | Substituted triazolopyridines having activity as MPS-1 inhibitors |
| BR112015030774A2 (en) * | 2013-06-10 | 2017-07-25 | Bayer Pharma AG | new compounds for cancer treatment |
| TWI770552B (en) | 2014-12-24 | 2022-07-11 | 美商基利科學股份有限公司 | Quinazoline compounds |
| CN107207498B (en) | 2014-12-24 | 2020-03-24 | 吉利德科学公司 | Fused pyrimidine compounds for the treatment of HIV |
| BR112017013440A2 (en) | 2014-12-24 | 2018-01-09 | Gilead Sciences, Inc. | isoquinoline compounds for the treatment of hiv |
| WO2017102091A1 (en) | 2015-12-18 | 2017-06-22 | Bayer Pharma Aktiengesellschaft | Heteroarylbenzimidazole compounds |
| WO2017207534A1 (en) | 2016-06-03 | 2017-12-07 | Bayer Pharma Aktiengesellschaft | Substituted heteroarylbenzimidazole compounds |
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- 2011-06-22 US US13/805,479 patent/US20130123271A1/en not_active Abandoned
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- 2011-06-22 WO PCT/EP2011/060445 patent/WO2011161159A1/en active Application Filing
- 2011-06-22 KR KR1020137001581A patent/KR20130116070A/en not_active Application Discontinuation
- 2011-06-22 CA CA2803496A patent/CA2803496A1/en not_active Abandoned
- 2011-06-22 EP EP11729591.5A patent/EP2585439A1/en not_active Withdrawn
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- 2011-06-22 JP JP2013515883A patent/JP2013533237A/en not_active Withdrawn
- 2011-06-22 NZ NZ605022A patent/NZ605022A/en not_active IP Right Cessation
- 2011-06-22 CN CN2011800407027A patent/CN103140480A/en active Pending
- 2011-06-22 AU AU2011268938A patent/AU2011268938A1/en not_active Abandoned
- 2011-06-22 EA EA201291329A patent/EA201291329A1/en unknown
-
2012
- 2012-12-18 IL IL223721A patent/IL223721A0/en unknown
- 2012-12-19 DO DO2012000317A patent/DOP2012000317A/en unknown
- 2012-12-19 CR CR20120653A patent/CR20120653A/en unknown
- 2012-12-19 TN TNP2012000610A patent/TN2012000610A1/en unknown
- 2012-12-20 NI NI201200193A patent/NI201200193A/en unknown
- 2012-12-20 GT GT201200345A patent/GT201200345A/en unknown
- 2012-12-21 CO CO12231930A patent/CO6660505A2/en not_active Application Discontinuation
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- 2012-12-21 CL CL2012003637A patent/CL2012003637A1/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| EA201291329A1 (en) | 2013-05-30 |
| TW201204723A (en) | 2012-02-01 |
| NI201200193A (en) | 2013-05-13 |
| TN2012000610A1 (en) | 2014-04-01 |
| AR081960A1 (en) | 2012-10-31 |
| CO6660505A2 (en) | 2013-04-30 |
| IL223721A0 (en) | 2013-03-05 |
| ECSP12012354A (en) | 2013-01-31 |
| WO2011161159A1 (en) | 2011-12-29 |
| NZ605022A (en) | 2013-12-20 |
| CA2803496A1 (en) | 2011-12-29 |
| US20130123271A1 (en) | 2013-05-16 |
| EP2585439A1 (en) | 2013-05-01 |
| MX2012015305A (en) | 2013-05-30 |
| AU2011268938A1 (en) | 2013-01-24 |
| MA34384B1 (en) | 2013-07-03 |
| PE20130640A1 (en) | 2013-03-30 |
| UY33461A (en) | 2012-01-31 |
| JP2013533237A (en) | 2013-08-22 |
| CL2012003637A1 (en) | 2013-07-05 |
| GT201200345A (en) | 2014-01-24 |
| CR20120653A (en) | 2013-04-03 |
| KR20130116070A (en) | 2013-10-22 |
| DOP2012000317A (en) | 2013-04-15 |
| SG186424A1 (en) | 2013-01-30 |
| BR112012032721A2 (en) | 2016-11-29 |
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